Pyrimidine derivatives and drugs

ABSTRACT

The object of the present invention is to obtain new class of compounds which have improving effect on learning and memory disorders with good selectivity in central nervous system and little side effects and then to provide a good medicine for treatment of dementia. 
     The present invention relates to the compounds represented by the following general formula or their pharmacologically acceptable salts and the drugs of improving learning or memory disorders comprising them as active ingredients. ##STR1## (wherein R 1  and R 2  are the same or different and are hydrogen, hydroxy, alkoxy, trifluoromethyl or halogen. A represents methyl, trifluoromethyl, or tert-butyl. Y represents O or NH.)

TECHNICAL FIELD

This invention relates to pyrimidine derivatives and theirpharmacologically acceptable salts represented by the following generalformula [I]. ##STR2## wherein A and B are as follows: When A represents##STR3## B represents methyl, trifluoromethyl, or tert-butyl; When Brepresents ##STR4## A represents methyl, trifluoromethyl, or tert-butyl.R¹ and R² are the same or different and each is a hydrogen atom, ahydroxy group, an alkoxy group, trifluoromethyl or halogen. R²represents (1), (2) or (3), represented by the following formulas.##STR5## wherein Y represents O or NH. ##STR6## wherein R⁴ and R⁵represent the following (a) or (b). (a) R⁴ and R⁵ are the same ordifferent and each is hydrogen or alkyl group.

(b) R⁴ and R⁵ link to form piperazino which is substituted with an arylgroup or an aralkyl group. ##STR7## wherein Y represents O or NH. m is 2or 3. R⁶ and R⁷ are the same or different and each is a hydrogen atom oran alkyl group, or form a 5 to 6 membered cyclic-amino group with theadjacent nitrogen atom. These cyclic-amino groups may include anothernitrogen, oxygen or sulfur atom, and moreover, those may be substitutedwith an aryl group with or without substituent(s), an aralkyl group withor without substituent(s), or an aroyl group with or withoutsubstituent(s).

Since the compounds of the present invention have improving effect onlearning and memory disorders with low toxicity as described later,those are useful as remedies for dementia etc.

BACKGROUND ART

According with the aging of the population, dementia have been adominant disease in the medication of the elderly patients. However, theremedies for the treatment of dementia have not been established.Cerebral metabolism enhancers, cerebral blood flow improving agents,tranquilizers. cholinomimetic agents and the like have been tried to usefor the treatment. However, the effect of these agents are notreproducible and insufficient. Therefore, better remedies for treatmenthave been required.

In the dementia of alzheimer type, a type of senile dementia, variousnervous systems are damaged. Especially, it has been reported thatcholinergic nervous systems, which play important roles in learning andmemory functions, are significantly damaged. Therefore, the developmentof central acethylcholinergic neuron enhancers have been an large streamof development in the improving agents for learning and memorydisorders. As for the acethylcholinergic neuron enhancers, precursors(such as choline and lecithin), choline esterase inhibitors ormuscarinic agonists have been developed so far. However, they are notsatisfactory enough.

On the other hand, various kinds of pyrimidine derivatives have beenreported.(for example, CA 93:45871w, 97:158036d, 98:34562y, 100:209733u,101:110856v, 102:162193s, 104:47176t, 107:236641p, 109:92924z and soforth). It is described in CA 100:209733u that the phleomycin amplifyingeffect of the compounds which have similar structures to the compoundsof the present invention. Also in CA 104:47176t, it is described thatthe plant's growth regulating effect of the compounds which have similarstructures to the compounds of the present invention.

However, up to this point, there have been no literatures describingthat the compounds of the present invention and analogous pyrimidinederivatives have improving effects on learning and memory disoders.

DISCLOSURE OF THE INVENTION

The inventors have studied in order to obtain the compounds which aresuperior to the conventionally known drugs for learning and memorydisorders in point of effectiveness, safety and durability.

Accordingly, the object of the present invention has been to obtain newcompounds which have improving effect on learning and memory disorderswith good selectivity in central nervous system and little side effectsand then to provide a good medicine for the treatment of dementia.

The gist of the present invention is in the chemical structure of thecompound itself which is represented by a general formula [I]. These arenot only new compounds which are not yet described in any literatures sofar, but also showing good pharmacological effects with low toxicity asdescribed later. However, the following compounds such as (i) to (x), asdescribed above, are known compounds which are already reported inliteratures.

However, in also these compounds, their excellent improving effects onlearing and memory disorder have been found for the first time by theinventors. Therefore, these compounds are also included in the presentinvention as the improving agents for learning and memory disorders.

(i) The compound wherein A is phenyl, B is methyl and R³ is ##STR8##(ii) The compound wherein A is phenyl, B is methyl and R³ is ##STR9##(iii) The compound wherein A is methyl, B is phenyl and R³ is ##STR10##(iv) The compound wherein A is methyl, B is phenyl and R³ is ##STR11##(v) The compound wherein A is methyl, B is phenyl and R³ is ##STR12##(vi) The compound wherein A is methyl, B is phenyl and R³ is --NH₂.

(vii) The compound wherein A is methyl, B is 4-chlorophenyl and R³ is--NH₂.

(viii) The compound wherein A is methyl, B is 4-methoxyphenyl and R³ is--NH₂.

(ix) The compound wherein A is phenyl, B is methyl and R³ is --NH₂.

(x) The compound wherein A is 4-chlorophenyl, B is methyl and R³ is--NH₂.

In the general fomula [I], as the alkoxy group represented by R¹ and R²,it is preferable to be straight or branched chain having 1 to 4 carbonatoms and illustrative of such alkoxys are methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy or sec-butoxy and so forth. The examplesof the halogens are chlorine, fluorine, bromine, iodine and the like.

As the alkyl groups represented by R⁴ and R⁵ it is preferable to bestraight or branched chain having 1 to 4 carbon atoms. And examples ofthe alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and the like.

As the aryl group which is a substituent of piperazino moietyrepresented by --NR⁴ R⁵, it is preferable to be ones having 6 to 12carbon atoms. And examples of the aryl are phenyl, α-naphthyl,β-naphthyl, biphenyl and so on, which is un-substituted or substitutedwith alkoxy group.

As the aralkyl groups, it is preferable to be ones having 7 to 14 carbonatoms. And examples of the aralkyl are benzyl, phenetyl, 3-phenylpropyl,naphthylmethyl, diphenylmethyl and so on, which is un-substituted orsubstituted with halogen(s).

As the alkyl groups represented by R⁶ and R⁷, it is preferable to beones described above.

As the 5 to 6 membered cyclic amino groups represented by --NR⁶ R⁷, itis preferable to be ones such as pyrrolidino, piperidino, piperazino,morpholino and thiomorpholino. As the aryl or aralkyl groups as thesubstituent group of the cyclic amino moiety, it is preferable to beones described above.

As the aroyl group, benzoyl un-substituted or substituted withalkoxy(ies) or halogen(s) is preferable.

Any reference to the compounds of the present invention, in addition tothe examples of compounds related to the process for productiondescribed later, there may be also mentioned the following examples ofcompounds.

4-[2-[4-[bis(4-fluorophenyl)methyl]piperazino]ethoxy]-6-methyl-2-phenylpyrimidine

4-[2-(4-diphenylmethylpiperazino)ethoxy]-2-phenyl-6-trifluoromethylpyrimidine

4-[2-[4-[bis(4-fluorophenyl)methyl]piperazino]ethoxy]-2-phenyl-6-trifluoromethylpyrimidine

4-[2-(4-diphenylmethylpiperazino)ethoxy]-2-(4-fluorophenyl)-6-trifluoromethylpyrimidine

4-[2-[4-[bis(4-fluorophenyl)methyl]piperazino]ethoxy]-2-(4-fluorophenyl)6-trifluoromethylpyrimidine

4-[2-(4-diphenylmethylpiperazino)ethoxy]-2-(4-trifluoromethylphenyl)6-trifluoromethylpyrimidine

4-[2-[4-[bis(4-fluorophenyl)methyl]piperazino]ethoxy]-2-(4-trifluoromethylphenyl)6-trifluoromethylpyrimidine

4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-phenyl-6-trifluoromethylpyrimidine

4-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-tert-butyl-2-(4-trifluoromethylphenyl)pyrimidine

4-(1-azabicyclo[2,2,2]octo-3-ylamino)-2-(4-methoxyphenyl)-6-methylpyrimidine

4-(1-azabicyclo[2,2,2]octo-3-ylamino)-2-(4-fluorophenyl)-6-methylpyrimidine

4-(1-azabicyclo[2,2,2]octo-3-ylamino)-2-(4-trifluoromethylphenyl)-5-methylpyrimidine

The compounds of the present invention can be produced for example, bythe following methods.

Method A: When R³ is ##STR13## (Wherein, A and B are the same as thedefined above, X is halogen. HNR¹¹ R¹² represents HNR⁴ R⁵, H₂ N(CH₂)_(m) NR⁶ R⁷ or ##STR14## R⁴ -R⁷ and m are the same as the definedabove.)

Method B: When R³ is ##STR15## (wherein, A, B, X, R⁶, R⁷ and m are thesame as the defined above.)

Method C: When R³ is --O--(CH₂)_(m) NR⁶ R⁷ or ##STR16## (wherein A, B,X, R⁶, R⁷ and m are the same as the defined above.)

Method A

[Ia] can be produced by the reaction of halogenopyrimidine [III] withamine [IV] in an inert solvent, in the presence of a base at 30° to 120°C., preferably 60° to 80° C.

As the reaction solvents, an aprotic polar solvent such as acetonitrile,dimethylsulfoxide, and N,N-dimethylformamide (DMF), alcohols such asmethanol, ethanol and isopropanol, ethers such as tetrahydrofuran,dimethoxyethane, diethylether and dioxane, glimes such asmethylcellosolve and ethyleneglycol dimethylether, halogenatedhydrocarbons such as methylene chloride and chloroform, hydrocarbonssuch as benzene, toluene and xylene, or the mixture of these solventscan be used.

As the bases, alkali carbonates (for example, potassium carbonate,sodium carbonate etc.), alkali bicarbonates (for example, potassiumbicarbonate, sodium bicarbonate etc.), inorganic salts of alkalihydroxides (for example, potassium hydroxide, sodium hydroxide etc.) orexcess amines (HNR¹¹ R¹²) can be used.

The reaction time is usually 4 to 24 hours, although it may varydepending on the kind of starting materials, bases and solvents used.

The amount of amine [IV] is preferably 1 to 1.2 moles per 1 mole of[III].

Method B

Either [Ib] or [Ic] can be produced by the reaction ofhalogenopyrimidine [III] with hydroxyalkylamine [V ] or quinuclidiol[V'] in an inert reaction solvent, in the presence of a catalyst at 0°to 80° C., preferably 10° to 30° C.

As the reaction solvents, N,N-dimethylformamide (DMF) or ethers such astetrahydrofuran, dimethoxyethane, diethylether, dioxane,diethyleneglycol and dimethylether, or the mixture of these solvents canbe used. As the catalysts, sodium hydride, sodium amide,potassium-tert-butoxide, butyllithium and the like can be used.

The reaction time is usually 2 to 24 hours although it may varydepending on the kind of starting materials, solvents and catalystsused.

The amount of hydroxyalkylamine [V ] or quinuclidiol [V'] is preferably1 to 1.2 moles per 1 mole of [III].

Method C

[Ib] or [Ic] can be produced by the reaction of hydroxypyrimidine [VI]with halogenoalkylamine [VII] or halogenoquinuclidine [VII'] in asolvent which is mentioned in method A, in the presence of a base at 0°to 80° C.

As the bases, sodium hydride, potassium carbonate, sodium hydroxide,potassium hydroxide and the like can be used.

The reaction time is usually 2 to 10 hours although it may varydepending on the kind of starting materials, bases and solvents used.

The amount of halogenoalkylamine [VII] or halogeno-quinucridine [VII']is preferably 1 to 1.2 moles per 1 mole [VI].

The starting materials of [III] and [IV], which are described in detailas the reference examples, can be produced as follows. ##STR17##(wherein A, B and X are the same as defined above. R is a lower alkyl.)

[VI] can be produced by the reaction of amidine [VII] with acylaceticacid ester [IX] in the presence of a base (inorganic salts such aspotassium carbonate and sodium carbonate , or organic salts such astriethylamine), in an inert solvent (for example, alcohols such asmethanol and ethanol, aprotic solvents such as acetonitrile andN,N-dimethylformamide.) at 60° to 140° C. for 5 to 24 hours. Inaddition, [III] can be prepared by heat-refluxing this with phosphorusoxychloride for 10 minutes to 1 hour.

Although there are some compounds in the present invention which possessasymmetric carbons, both optical isomers of each compound and theirracemic mixtures are included in the present invention. The opticalisomers can be obtained by optically resolution of their racemicmixtures based upon their basicity with the use of optical active acids(such as tartaric acid, dibenzoyltartaric acid, mandeiic acid10-camphor-sulfonic acid) according to conventional methods, or by usingoptically active compounds, [IV], [V'] and [VII'] prepared previously asraw materials.

The desired compound [I] produced by this manner can be isolated andpurified in the form of free base or acid additional salt, for example,by concentration, change of liquid property, transference of solute,solvent extraction, crystallization, fractional distillation,chromatography etc. according to the known method per se.

The acid additional salts can include the salts of mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid, and the salts of organic acids such as acetic acid,citric acid tartaric acid, maleic acid, succinic acid, fumaric acid,p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid.

when the compounds of the present invention are given as medicines,those are administered to animals including human, as it is or aspharmaceutical compositions which contains the compounds for theconcentration of, for example, 0.1 to 99.5%, preferably 0.5 to 90% inpharmaceutically acceptable carriers which are nontoxic and inert.

As the carriers, more than one kind of diluents, filling materials andother supplementary substances for prescription in the forms of solid,semi-solid or liquid states are used. It is preferable thatpharmaceutical compositions are administered as a unit dosage form. Thepharmaceutical compositions of the present invention can be administeredorally, intra-tissue, locally (such as percutaneous administration etc.)or per rectum. It is the matter of course that those should beadministered in suitable form depending on the way of administration.

Although it is preferable that the doses as the improving agents forlearning and memory disorders should be controlled considering thepatient's condition such as age and body weight and so on,administration route, and disposition and degree of the diseases etc.,it is general ranges that one-day dose of the effective constituent inthe present invention for adults is usually 0.1 mg to 1 g/human,preferably 1 to 300 mg/human. Depending on the cases, sometimes the dosebelow the above dose range is enough, or contrary, some requires moredose than the range. It is also preferable to administer in divideddoses by 2 to 4 times a day.

Oral administration can be carried out using solid or liquid unit dosagesuch as fine powder, powder formulations, tablets, sugar-coating drugs,capsules, granules, suspensions, liquid preparations, syrups, drops,sublingual tablets and other formulations.

Fine powders are produced by pulverizing the active substances to beadequately fine. Powder formulation are prepared by pulverizing theactive substances to be adequately fine and admixing with similarlypulverized pharmaceutical carriers, for example, edible carbohydratessuch as starch or mannitol, and the others. If necessary, it may beadmixed with flavoring agents, preservatives, dispersing agents,coloring agents, perfume and the others.

Capsules are produced by filling fine powders or powder formulationwhich are previously pulverized as the mentioned above, or granulatedsubstances as mentioned in the section of tablets, into capsuleinteguments such as gelatin capsule. The pulverized substances areadmixed with lubricants or fluidifying agents such as colloidal silica,talc, magnesium stearate and potassium stearate as well as solidpolyethyleneglycol, and then the filling procedure can be carried out.The effectiveness of drugs when the capsule is taken can be improved, ifdisintegrators or solubilizing agents such as carboxymethylcellulose,calcium carboxymethyl cellulose, lower substituted hydroxypropylcellulose, sodium croscarmellose, sodium carboxymethyl starch, calciumcarbonate and sodium carbonate are added into the powder.

Moreover, soft capsule can be prepared by suspending and dispersing thefine powder of this product in vegetable oil, polyethyleneglycol,glycerin or surfactants and then wrapping this with gelatin sheets.Tablets can be produced the way that powdery mixtures is prepared byadding filler, then it is granulated or slugged, and then compressedafter addition of disintegrator or lubricant. The powder mixtures areprepared by admixing the suitably pulverized substance with the abovementioned diluents and bases, and if necessary, binders (for example,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, gelatin, polyvinylpyrolidone,polyvinylalcohol and the like), reabsorbing agents (for example,quaternary salts) and adsorbing agents (for example, bentonite, kaolin,dicalcium phosphate and the like) may be used simultaneously in thisprocedure. The powdery mixture can be changed to granule by the way thatfirst it is moistened with binders, for example, syrup, starch paste,acacia, cellulose solution or high polymer solution, and then it isstirred to mix, dried and pulverized. In stead of granulating the powderin this way, it is possible to make granule by pulverizing theincomplete form of slug which is obtained after the previous compressionby the compressor.

The granule made by this way can be prevented from mutual adhering byadding lubricants such as stearic acid, stearate, talk and mineral oil.The mixture lubricated in this way is subsequently compressed. The baretablets made in this manner can be given film-coating or sugar-coating.

The drugs may be directly compressed after mixing with fluid inactivecarrier without the process of granulation and slugging. The transparentor semitransparent protecting film which is consisted of sealing-up filmmade from shellac, the film made from sugar and high polymer, and thethings like rubbing-up film consisted of wax can also be used.

Other oral dosage formulation such as solutions, syrups and elixirs canbe also made as unit dosage form which contain a constant dose of drugin a constant amounts of the formulation. Syrups are produced bydissolving compounds in suitable perfumed water and elixirs are producedby using nontoxic alcohol carriers. Suspensions is prescribed bydispersing a compound in nontoxic carriers. It is also possible to addsolubilizing agents or emulsifying agents (for example,ethoxylated-isostearylalcohols or polyoxyethylenesorbitol esters),preservatives, flavoring agents (for example, peppermint oil orsaccharin) and the others, when required.

If necessary, the prescription of unit dosage for oral administrationmay be as microcapsulated formulation. The said prescription can alsoprovide prolongation of action time and lasting release of drugs byfilm-coating and filling up into high polymer wax and the like.

Intra-tissue administrations can be carried out using liquid unit dosageform, such as the form of solution and suspension which are prepared forsubcutaneous, intramuscular or intravenous injections. Theseformulations are produced by the way that a certain amount of compoundis suspended or dissolved in nontoxic liquid carriers such as aqueous oroily vehicles which are suitable for the purpose of injection, and thenthe said suspension or solution is sterilized. Nontoxic salts or thesalt-solution may be added to them in order to isotonize the injections.In addition, stabilizers, preservatives, emulsifiers and the like can beused at the same time with them.

Rectal administration can be carried out using suppositories and thelikes which are produced by dissolving or suspending compounds inwater-soluble or insoluble solids with low melting point, for example,polyethyleneglycol, cacao butter, semisynthetic fats and oils (such aswitepsol, a registered trademark), higher esters (such asmyristilpalmitate) and their mixture.

THE BEST MODE FOR PRACTICING THE INVENTION

The present invention will be further illustrated by giving referenceexamples, examples, test examples and pharmaceutical examples of thecompound of the present invention hereinafter.

Reference Example 1

Preparation of 4-hydroxy-2-(4-methoxyphenyl)-6-methyl-pyrimidine

(1) Preparation of 4-methoxybenzimidic acid methylester hydrochloride

25 g of anisonitril was dissolved in 250 ml of methanol. Aftersaturation with hydrogen chloride gas under cooling in ice-water andstirring, the solution was stirred at room temperature for 15 hours.Then, methanol was evaporated in vacuo. Ether was added to the residueand the crystals were filtered off and dried. Whereby 35.9 g of thedesired substance was obtained as white crystals. Melting point is 111°to 112° C. (Decomposition).

(2) Preparation of 4-methoxybenzamidine hydrochloride

35.9 g of 4-methoxybenzimidic acid methylester hydrochloride wasdissolved in 300 ml of methanol. After saturation with ammonia gas undercooling in ice-water and stirring, the solution was stirred at roomtemperature for 15 hours. Then, methanol was evaporated in vacuo. Ethylacetate was added to the residue. The precipitated crystals werefiltered off and dried. Whereby 30.9 g of the desired substance wasobtained as white crystals. Melting point is 220° to 221° C.

(3) Preparation of 4-hydroxy-2-(4-methoxyphenyl)-6-methylpyrimidine

To the mixture of 10 g of 4-methoxybenzamidine hydrochloride, 7.7 g ofethyl acetoacetate and 16.3 g of potassium carbonate were added 120 mlof ethanol, and the mixture was heat-refluxed with stirring for 7 hours.The reaction mixture was cooled and filtered to remove insolublesubstances. The filtrate was evaporated. Water was added to the residueto dissolve and then the resulting solution was neutralized with aceticacid. The precipitated crystals were filtered off, washed with water anddried. Whereby 10.9 g of the desired substance was obtained as whitecrystals. Melting point is 202° to 203° C.

In the same way, the following compounds were obtained.

2-(4-fluorophenyl)-4-hydroxy-6-methylpyrimidine. Melting point is 224°to 225.5° C.

4-hydroxy-2-(4-methoxyphenyl)-6-trifluoromethylpyrimidine. Melting pointis 239° to 240.5° C.

4-hydroxy-6-methyl-2-(4-trifluoromethylphenyl)pyrimidine. Melting ispoint 222° to 224° C.

Reference Example 2 Preparation of4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine

6.5 g of 4-hydroxy-2-(4-methoxyphenyl)-6-methylpyrimidine prepared inreference example 1 (3) was added to 30 ml of phosphorus oxychloride,and the mixture was refluxed with stirring for 30 minutes. The reactionmixture was cooled and poured into diluted ammonia solution and theprecipitated crystals were filtered off. The crystals were dissolved inchloroform. After the chloroform layer was washed twice with water, itwas dried with anhydrous magnesium sulfate and was evaporated in vacuo.The residue was crystallized with n-hexane and filtered off. Whereby 5.1g of crystals was obtained. Melting point is 80° to 81° C.

In the same way, the following compounds were obtained.

4-chloro-2-(4-fluorophenyl)-6-methylpyrimidine. Melting point is 87° to88.5° C.

4-chloro-2-(4-methoxyphenyl)-6-trifluoromethylpyrimidine. Melting pointis 54° to 56° C.

4-chloro-6-methyl-2-(4-trifluoromethylphenyl)pyrimidine. Melting pointis 66° to 67° C.

Reference Example 3 Preparation of4-hydroxy-6-(4-methoxyphenyl)-2-methylpyrimidine

1.89 g of acetamidine hydrochloride and 4.44 g of etylparamethoxybenzoylacetate were dissolved in 40 ml of ethanol. Afteraddition of 5.52 g of potassium carbonate, the solution was refluxedwith stirring for 8 hours, and then evaporated in vacuo. 5 g of sodiumhydroxide was dissolved in 30 ml of water and this was added to theevaporated residue. Add ether, then extract, the aqueous layer wasneutralized with acetic acid. The resulting precipitations were filteredoff, washed with water and dried. Then 1.1 g of crystals were obtained.Melting point is 270° to 272° C.

Reference Example 4 Preparation of4-chloro-6-(4-methoxyphenyl)-6-methylpyrimidine

9 g of 4-hydroxy-6-(4-methoxyphenyl)-2-methylpyrimidine was added to 60ml of phosphorus oxychloride and the mixture was refluxed with stirringfor 30 minutes. The reaction mixture was added to diluted ammoniasolution little by little, and the precipitate was filtered. This wasdissolved in chloroform and washed with potassium carbonate solution.After washing, the chloroform layer was dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was crystallized withn-hexane and filtered off. Whereby 5.78 g of the crystals were obtained.Melting point is 65° to 67° C.

EXAMPLE 14-(1-azabicyclo[2,2,2]-octo-3-yloxy)-2-(4-methoxyphenyl)-6-methylpyrimidinemaleate

15.0 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine and 8.13 g of3-quinuclidinol were dissolved in 150 ml of N,N-dimethylformamide. Then2.56 g of 60% sodium hydride was added to the solution under ice-coolingand stirring. After stirring for 2 hours under ice-cooling andadditionally for 5 hours at room temperature, the reaction mixture waspoured into ice-water and the oily substance was extracted with ethylacetate. After the ethyl acetate layer was washed twice with water, itwas dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was applied to a column chromatography with silica gel (Wako gelC-200 500 g, elution with chloroform and 3% methanol-chloroform inorder), then 16.9 g of oily substance was obtained. This was dissolvedin 100 ml of methanol, methanol solution of 6.0 g of maleic acid wasadded. After stirring, the solution was evaporated in vacuo. Ether wasadded to the residue to crystallize then the crystals were filtered off.Whereby 16.4 g of the crystals were obtained. These were recrystallizedwith ethanol, whereby 12.6 g of the crystals were obtained. Meltingpoint is 163° to 164° C.

Elementary analysis for (C₁₉ H₂₂ N₃ O₂ · C₄ H₄ O₄ 441.48)

Calculated (%) C:62.57 H:6.16 N:9.52

Found (%) C:62.51 H:6.40 N:9.61

EXAMPLE 2(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-methoxyphenyl)-6-methylpyrimidinemaleate

1 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine was dissolved intetrahydrofuran 15 ml and DMF 10 ml. After addition of 542 mg of(R)-(+)-3-quinuclidinol thereto, 340 mg of 60% sodium hydride was addedto the solution under ice-cooling and stirring. After stirring for 2hours under ice-cooling and additionally for 17 hours at roomtemperature, the reaction mixture was poured into ice-water andextracted with ethyl acetate. After the ethyl acetate layer wasextracted with diluted hydrochloride solution, the aqueous layer wasneutralized with an aqueous sodium hydroxide solution. Then this wasextracted with ethyl acetate. After washing the ethyl acetate layer withwater and drying with anhydrous magnesium sulfate, the solvent wasevaporated in vacuo. The resulting yellow crystals were purified withcolumn chromatography with silica gel(Wako gel C-200 20 g, elution withchloroform and 3% methanol-chloroform in order), then 590 mg of whitecrystals were obtained.

After the crystal was dissolved in methanol and added maleic acid 211mg/methanol 2 ml, ether was added and the precipitated crystals wasfiltered off. This was recrystallized with acetonitrile/ether mixedsolution. Whereby 624 mg of the desired compound was obtained as whitecrystal. Melting point is 158.5° to 159.5° C.

Elementary analysis for (C₁₉ H₂₃ N₂ O₂ · C₄ H₄ O₄)

Calculated (%) C:62.57 H:6.16 N:9.52

Found (%) C:62.88 H:6.16 N:9.52

Specific rotation [α]_(D) (20° C.)=-33.2 (c=1, H₂ O)

EXAMPLE 34-[2-(4-diphenylmethylpiperazino)ethoxy]-2-(4-methoxyphenyl)-6-methylpyrimidine

0.6 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine and 0.76 g of1-diphenylmethyl-4-(2-hydroxyethyl)piperazine were dissolved in 20 ml ofdried tetrahydrofuran. After addition of 0.1 g of 60% sodium hydride,the mixture was stirred for 20 hours at room temperature. The reactionmixture was poured into ice-water and was extracted with ethyl acetate.After the extract was washed with water and was dried with anhydrousmagnesium sulfate, then was evaporated in vacuo. The resulting residuewas purified with column chromatography with silica gel (Wako gel C-200,elution with chloroform and then chloroform:ethyl acetate=8:1). Thedesired fraction was crystallized by evaporating the solvent underreduced pressure. The crystals were recrystallized with the solventmixed with chloroform and ether, resulting to obtain 0.6 g of crystals.Melting point is 132° to 133° C.

Elementary analysis for (C₃₁ H₃₄ N₄ O₂)

Calculated (%) C:75.28 H:6.93 N:11.33

Found (%) C:74.95 H:7.03 N:11.24

EXAMPLE 44-(4-diphenylmethylpiperazino)-2-(4-methoxyphenyl)-6-methylpyrimidine

1.17 g of 4-chloro-2-(4-methoxyphenyl)-6-methylpyrimidine and 1.38 g of1-diphenylmethylpiperazine were dissolved in 20 ml ofN,N-dimethylformamide. After the addition of 1 g of potassium carbonate,the mixture was stirred for 6 hours at 80° to 85° C. The reactionmixture was poured into ice-water, then the resulting crystals werefiltered off, washed with water and dried. Whereby 2.2 g of crystalswere obtained. 1.85 g of the crystals were obtained by recrystallizingwith ethanol. Melting point is 147° to 149° C.

Elementary analysis for (C₂₉ H₃₀ N₄ O)

Calculated (%) C:77.30 H:6.71 N:12.43

Found (%) C:77.46 H:6.89 N:12.24

EXAMPLE 5 4-(4-methoxyphenyl)-2-methyl-6-(2-piperidinoethoxy)pyrimidinedihydrochloride

1.17 g of 4-chloro-6-(4-methoxyphenyl)-2-methylpyrimidine and 0.65 g of2-piperidinoethanol were dissolved in 10 ml of dried tetrahydrofuran.After the addition of 60% sodium hydride 0.2 g, the mixture was stirredfor 3 hours at room temperature. The reaction mixture was poured intoice-water, and then was extracted with ethyl acetate. The extract waswashed with water and was dried with anhydrous magnesium sulfate, andthen this was evaporated in vacuo. The residue was purified with columnchromatography with silica gel(Wako gel c-200 150 g, elution withchloroform and then chloroform: methanol=99:1), resulting 1.3 g of oilysubstance. This was dissolved in 10 ml of ethanol, 3 ml of 20% ethanolhydrochloride was added and evaporated in vacuo. Ether was added to theresidue to crystallize. Whereby 1.32 g of crystals were obtained. Thesewere recrystallized with isopropanol, resulting to obtain 0.83 g ofcrystals. Melting point is 165° to 167° C.

Elementary analysis for (C₁₉ H₂₅ N₂ O ·2HCl)

Calculated (%) C:57.00 H:6.80 N:10.50

Found (%) C:57.28 H:6.94 N:10.31

In the same way as mentioned in practice example to 5, the followingcompounds were prepared.

EXAMPLE 6 4-[2-(N,N-diethylamino)ethoxy]-6-methyl-2-phenylpyrimidinedihydrochloride

Melting point 150°-153° C.

Elementary analysis for (C₁₇ H₂₃ N₃ O₂ · 2HCl)

Calculated (%) C:56.99 H:7.03 N:11.73

Found (%) C:56.73 H:6.98 N:11.67

EXAMPLE 7 4-[2-(N,N-dimethylamino)ethoxy]-6-methyl-2-phenylpyrimidinedihydrochloride

Melting point 184°-186° C.

Elementary analysis for (C₁₅ H₁₉ N₃ O · 2HCl)

Calculated (%) C:54.55 H:6.41 N:12.72

Found (%) C:54.31 H:6.78 N:12.56

EXAMPLE 8 4-Methyl-2-phenyl-6-(2-piperidinoethoxy) pyrimidinedihydrochloride

Melting point 179°-181° C.

Elementary analysis for (C₁₈ H₂₃ N₃ O · 2HCl)

Calculated (%) C:58.38 H:6.80 N:11.35

Found (%) C:58.13 H:6.96 N:11.14

EXAMPLE 9 4-Methyl-2-phenyl-6-(2-morpholinoethoxy)pyrimidinedihydrochloride

Melting point 181°-182° C.

Elementary analysis for (C₁₇ H₂₁ N₃ O₂ · 2HCl)

Calculated (%) C:54.85 H:6.23 N:11.29

Found (%) C:54.61 H:6.48 N:11.46

EXAMPLE 10 4-Methyl-2-phenyl-6-(3-piperidinopropoxy)pyrimidinedihydrochloride

Melting point 175°-177° C.

Elementary analysis for (C₁₉ H₂₅ N₃ O · 2HCl)

Calculated (%) C:59.38 H:7.08 N:10.98

Found (%) C:59.29 H:7.23 N:10.97

EXAMPLE 11 4-Methyl-2-phenyl-6-[2-(4-phenylpiperazino)ethoxy] pyrimidinemaleate

Melting point 172°-173° C.

Elementary analysis for (C₂₃ H₂₆ N₄ O · C₄ H₄ O₄)

Calculated (%) C:66.11 H:6.16 N:11.42

Found (%) C:66.33 H:6.01 N:11.53

EXAMPLE 124-[2-[4-(4-methoxyphenyl)piperazino]ethoxy]-6-methyl-2-phenylpyrimidinemaleate

Melting point 128°-129° C.

Elementary analysis for (C₂₄ H₂₈ N₄ O₂ · C₄ H₄ O₄)

Calculated (%) C:64.60 H:6.20 N:10.76

Found (%) C:64.70 H:6.19 N:10.75

EXAMPLE 134-[2-(4-diphenylmethylpiperazino)ethoxy]-6-methyl-2-phenylpyrimidine

Melting point 113°-115° C.

Elementary analysis for (C₃₀ H₃₂ N₄ O)

Calculated (%) C:77.56 H:6.94 N:12.06

Found (%) C:77.69 H:7.14 N:12.00

EXAMPLE 144-[3-(4-diphenylmethylpiperazino)propoxy]-6-methyl-2-phenylpyrimidinedimaleate

Melting point 174°-175° C.

Elementary analysis for (C₃₁ H₃₄ N₄ O · 2C₄ H₄ O₄)

Calculated (%) C:65.90 H:5.95 N:7.88

Found (%) C:66.09 H:6.18 N:8.09

EXAMPLE 154-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-methyl-2-phenylpyrimidine maleate

Melting point 176°-177° C.

Elementary analysis for (C₁₈ H₂₁ N₃ O · C₄ H₄ O₄)

Calculated (%) C:64.22 H:6.12 N:10.21

Found (%) C:64.36 H:6.17 N:10.08

EXAMPLE 164-[2-(N,N-diethylamino)ethoxy]-2-(4-methoxyphenyl)-6-methylpyrimidinedihydrochloride

Melting point 182°-184° C.

Elementary analysis for (C₁₈ H₂₅ N₃ O₂ · 2HCl)

Calculated (%) C:55.67 H:7.01 N:10.82

Found (%) C:55.83 H:7.04 N:10.90

EXAMPLE 174-[2-(N,N-dimethylamino)ethoxy]-2-(4-methoxyphenyl)-6-methylpyrimidinedihydrochloride

Melting point 197°-198° C.

Elementary analysis for (C₁₆ H₂₁ N₃ O₂ · 2HCl)

Calculated (%) C:53.34 H:6.43 N:11.66

Found (%) C:53.57 H:6.78 N:11.64

EXAMPLE 18 2-(4-methoxyphenyl)-4-methyl-6-(2-piperidinoethoxy)pyrimidinedihydrochloride

Melting point 179°-181° C.

Elementary analysis for (C₁₉ H₂₅ N₃ O₂ · 2HCl)

Calculated C:57.00 H:6.80 N:10.50

Found (%) C:56.90 H:6.99 N:10.37

EXAMPLE 19 2-(4-methoxyphenyl)-4-methyl-6-(2-morpholinoethoxy)pyrimidinedihydrochloride

Melting point 206°-209° C.

Elementary analysis for (C₁₈ H₂₃ N₃ O₃ · 2HCl)

Calculated (%) C:53.74 H:6.26 N:10.44

Found (%) C:53.72 H:6.41 N:10.47

EXAMPLE 202-(4-methoxyphenyl)-4-methyl-6-(3-piperidinopropoxy)pyrimidinedihydrochloride

Melting point 187°-188° C.

Elementary analysis for (C₂₀ H₂₇ N₃ O₂ · 2HCl)

Calculated (%) C:57.97 H:7.05 N:10.14

Found (%) C:57.88 H:7.19 N:10.08

EXAMPLE 21 2-(4-methoxyphenyl)-4-methyl-6-[2-(4-phenylpiperazino)ethoxy]pyrimidine

Melting point 83°-85° C.

Elementary analysis for (C₂₄ H₂₆ N₄ O₂)

Calculated (%) C:71.26 H:6.98 N:13.85

Found (%) C:71.22 H:7.11 N:13.77

EXAMPLE 222-(4-methoxyphenyl)-4-[2-[4-(4-methoxyphenyl)piperazino]ethoxy]6-methylpyrimidinemaleate

Melting point 149°-150° C.

Elementary analysis for (C₂₅ H₃₀ N₄ O₃ · C₄ H₄ O₄)

Calculated (%) C:63.26 H:6.22 N:10.18

Found (%) C:63.36 H:6.17 N:10.15

EXAMPLE 23 2-(4-methoxyphenyl)-4-methyl-6-[2-(4-phenylpiperidino)ethoxy]pyrimidine dihydrochloride

Melting point 151°-155° C.

Elementary analysis for (C₂₅ H₂₉ N₃ O₂ · 2HCl)

Calculated (%) C:63.02 H:6.56 N:8.82

Found (%) C:62.86 H:6.37 N:8.98

EXAMPLE 244-[2-[4-(4-chlorobenzoyl)piperazino]ethoxy]-2-(4-methoxyphenyl)6-methylpyrimidine maleate

Melting point 164°-165° C.

Elementary analysis for (C₂₅ H₂₇ ClN₄ O₂ · C₄ H₄ O₄)

Calculated (%) C:59.74 H:5.36 N:9.61

Found (%) C:59.40 H:5.46 N:9.59

EXAMPLE 254-[2-[4-(4-methoxybenzoyl)piperazino]ethoxy]-2-(4-methoxyphenyl)6-methylpyrimidine maleate

Melting point 156°-157° C.

Elementary analysis for (C₂₆ H₃₀ N₄ O₄ · C₄ H₄ O₄)

Calculated (%) C:62.27 H:5.92 N:9.68

Found (%) C:62.11 H:6.14 N:9.67

EXAMPLE 264-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)-6-methylpyrimidinemaleate

Melting point 141.5°-143° C.

Elementary analysis for (C₁₈ H₂₀ FN₃ O · C₄ H₄ O₄)

Calculated (%) C:61.52 H:5.63 N:9.78

Found (%) C:61.74 H:5.92 N:9.71

EXAMPLE 27(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)6-methylpyrimidine maleate

Melting point 155.5°-156.5° C.

Elementary analysis for (C₁₈ H₂₀ FN₃ O · C₄ H₄ O₄)

Calculated (%) C:61.52 H:5.63 N:9.78

Found (%) C:61.30 H:5.92 N:9.81

Specific rotation [α]_(D) (20° C.)=-18.69 (c=1, H₂ O)

(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)6-methylpyrimidine hydrochloride

Melting point 277°-278° C.

Elementary analysis for (C₁₈ H₂₀ FN₃ O · HCl)

Calculated (%) C:61.80 H:6.05 N:12.01

Found (%) C:61.57 H:5.95 N:12.08

Specific rotation [α]_(D) (20° C.)=-24.77 (c=1, H₂ O)

EXAMPLE 28(S)-(+)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-methoxyphenyl)6-methylpyrimidine maleate

Melting point 159°-161° C.

Elementary analysis for (C₁₉ H₂₃ N₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:62.57 H:6.16 N:9.52

Found (%) C:62.30 H:6.34 N:9.71

Specific rotation [α]_(D) (20° C.)=+32.5 (c=1, H₂ O)

EXAMPLE 294-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl)-6-methylpyrimidinemaleate

Melting point 161°-162°-C.

Elementary analysis for (C₁₈ H₂₀ ClN₃ O · C₄ H₄ O₄)

Calculated (%) C:59.26 H:5.43 N:9.42

Found (%) C:59.30 H:5.38 N:9.37

EXAMPLE 30 4-methylamino-6-methyl-2-phenylpyrimidine

Melting point 69°-71° C.

Elementary analysis for (C₁₂ H₁₃ N₃)

Calculated (%) C:72.33 H:6.57 N:21.09

Found (%) C:72.36 H:6.69 N:21.14

EXAMPLE 31 4-(N,N-diethylamino)-6-methyl-2-phenylpyrimidinehydrochloride

Melting point 161°-163° C.

Elementary analysis for (C₁₅ H₁₉ N₃ · HCl)

Calculated (%) C:64.85 H:7.26 N:15.13

Found (%) C:64.69 H:7.43 N:15.37

EXAMPLE 32 4-methyl-6-(2-morpholinoethylamino)-2-phenylpyrimdinedihydrochloride

Melting point 251°-253.5° C.

Elementary analysis for (C₁₇ H₂₂ N₄ O · 2HCl)

Calculated (%) C:54.99 H:6.51 N:15.09

Found (%) C:55.14 H:6.38 N:15.38

EXAMPLE 334-[2-(N,N-diisopropylamino)ethylamino]-6-methyl-2-phenylpyrimidinedihydrochloride

Melting point 255°-256° C.

Elementary analysis for (C₁₉ H₂₈ N₄ · 2HCl)

Calculated (%) C:59.21 H:7.84 N:14.54

Found (%) C:59.43 H:7.66 N:14.68

EXAMPLE 34 4-methyl-6-(4-phenylpiperazino)-2-phenylpyrimidine

Melting point 95°-97° C.

Elementary analysis for (C₂₁ H₂₂ N₄)

Calculated (%) C:76.33 H:6.71 N:16.95

Found (%) C:76.16 H:6.82 N:16.69

EXAMPLE 35 4-(4-diphenylmethylpiperazino)-6-methyl-2-phenylpyrimidine

Melting point 201°-203° C.

Elementary analysis for (C₂₈ H₂₈ N₄)

Calculated (%) C:79.97 H:6.71 N:13.32

Found (%) C:79.99 H:6.88 N:13.12

EXAMPLE 36 4-amino-2-(4-methoxyphenyl)-6-methylpyrimidine

Melting point 177°-180° C.

Elementary analysis for (C₁₂ H₁₃ N₃ O)

Calculated (%) C:66.96 H:6.09 N:19.52

Found (%) C:67.09 H:6.20 N:19.42

EXAMPLE 37 2-(4-methoxyphenyl)-4-methyl-6-methylaminopyrimidine

Melting point 99°-101° C.

Elementary analysis for (C₁₃ H₁₅ N₃ O)

Calculated (%) C:68.10 H:6.59 N:18.33

Found (%) C:68.50 H:6.76 N:18.41

EXAMPLE 38 2-(4-methoxyphenyl)-4-methyl-6-(2-morpholinoethylamino)pyrimidine

Melting point 144°-146° C.

Elementary analysis for (C₁₈ H₂₄ N₄ O₂)

Calculated (%) C:65.83 H:7.37 N:17.06

Found (%) C:65.69 H:7.45 N:16.82

EXAMPLE 39 4-[2-(N,N-diethylamino)ethoxy]-2-methyl-6-phenylpyrimidinedihydrochloride

Melting point 195°-197° C.

Elementary analysis for (C₁₇ H₂₃ N₂ O · 2HCl)

Calculated (%) C:56.99 H:7.03 N:11.73

Found (%) C:56.90 H:7.19 N:11.75

EXAMPLE 40 4-[2-(4-diphenylmethylpiperazino)ethoxy]-2-methyl-6-phenylpyrimidine

Melting point 129°-130° C.

Elementary analysis for (C₃₀ H₃₂ N₄ O)

Calculated (%) C:77.56 H:6.94 N:12.06

Found (%) C:77.38 H:7.15 N:11.92

EXAMPLE 414-[2-(N,N-diethylamino)ethoxy]-6-(4-methoxyphenyl)-2-methylpyrimidinedihydrochloride

Melting point 168°-171° C.

Elementary analysis for (C₁₈ H₂₅ N₃ O₂ · 2HCl)

Calculated (%) C:55.67 H:7.01 N:10.82

Found (%) C:55.49 H:6.83 N:10.98

EXAMPLE 424-[2-(4-diphenylmethylpiperazino)ethoxy]-6-(4-methoxyphenyl)-2-methylpyrimidine

Melting point 131°-133° C.

Elementary analysis for (C₃₁ H₃₄ N₄ O₂)

Calculated (%) C:75.28 H:6.93 N:11.33

Found (%) C:74.77 H:7.00 N:11.24

EXAMPLE 434-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-(4-methoxyphenyl)-2-methylpyrimidinemaleate

Melting point 145°-147° C.

Elementary analysis for (C₁₉ H₂₃ N₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:62.57 H:6.16 N:9.52

Found (%) C:62.30 H:6.34 N:9.62

EXAMPLE 44 (R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl)6-methylpyrimidine maleate

Melting point 166°-167° C.

Elementary analysis for (C₁₈ H₂₀ ClN₃ O · C₄ H₄ O₄)

Calculated (%) C:59.26 H:5.43 N:9.42

Found (%) C:59.10 H:5.34 N:9.61

Specific rotation [α]_(D) (20° C.)=-35.03 (c=1, H₂ O)

EXAMPLE 45 2-methyl-4-(2-morpholinoethylamino)-6-phenylpyrimidinedihydrochloride

Melting point 277°-282° C.

Elementary analysis for (C₁₇ H₂₂ N₄ O)

Calculated (%) C:54.99 H:6.51 N:15.09

Found (%) C:54.81 H:6.63 N:14.90

EXAMPLE 46 4-(4-diphenylmethylpiperazino)-2-methyl-6-phenylpyrimidine

Melting point 195°-198° C.

Elementary analysis for (C₂₈ H₂₈ N₄)

Calculated (%) C:79.96 H:6.71 N:13.32

Found (%) C:79.73 H:6.89 N:13.23

EXAMPLE 47(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl)6-methylpyrimidine hydrochloride

Melting point 284°-285.5° C.

Elementary analysis for (C₁₈ H₂₀ ClN₃ O · HCl)

Calculated (%) C:59.02 H:5.78 N:11.47

Found (%) C:58.79 H:5.66 N:11.51

Specific rotation [α]_(D) (20° C.)=-21.47 (c=1, H₂ O)

EXAMPLE 484-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-methoxyphenyl)-6-trifluoromethylpyrimidinemaleate

Melting point 173°-174.5° C.

Elementary analysis for (C₂₃ H₂₄ F₃ N₃ O₆)

Calculated (%) C:55.76 H:4.88 N:8.48

Found (%) C:55.83 H:5.07 N:8.55

EXAMPLE 494-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-methyl-2-(4-trifluoromethylphenyl)pyrimidine maleate

Melting point 173.5°-174.5° C.

Elementary analysis for (C₂₃ H₂₄ F₃ N₃ O₅)

Calculated (%) C:57.62 H:5.05 N:8.76

Found (%) C:58.00 H:5.14 N:8.90

EXAMPLE 504-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-trifluoromethylphenyl)6-trifluoromethylpyrimidine maleate

Melting point 171°-172° C.

Elementary analysis for (C₁₉ H₁₇ F₆ N₃ O · C₄ H₄ O₄)

Calculated (%) C:51.79 H:3.97 N:7.88

Found (%) C:51.88 H:4.03 N:7.93

EXAMPLE 514-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)-6-trifluoromethylpyrimidinemaleate

Melting point 176°-177.5° C.

Elementary analysis for (C₁₉ H₁₇ F₄ N₂ O · C₄ H₄ O₄)

Calculated (%) C:54.66 H:4.38 N:8.69

Found (%) C:54.44 H:4.42 N:8.76

EXAMPLE 524-[2-(4-diphenylmethylpiperazino)ethoxy]-2-(4-fluorophenyl)-6-methylpyrimidine

Melting point 120°-121.5° C.

Elementary analysis for (C₃₀ H₃₁ FN₄ O)

Calculated (%) C:74.66 H:6.47 N:11.61

Found (%) C:74.58 H:6.62 N:11.51

EXAMPLE 534-[2-[4-[bis(4-fluorophenyl)methyl]piperazino]ethoxy]-2-(4-methoxyphenyl)6-methylpyrimidine

Melting point 125°-126° C.

Elementary analysis for (C₃₁ H₃₂ F₂ N₄ O₂)

Calculated (%) C:70.17 H:6.08 N:10.56

Found (%) C:70.11 H:6.06 N:10.55

EXAMPLE 544-[2-(4-diphenylmethylpiperazino)ethoxy]-6-methyl-2-(4-trifluoromethylphenyl)pyrimidine

Melting point 161.5°-162.5° C.

Elementary analysis for (C₃₁ H₃₁ F₃ N₄ O)

Calculated (%) C:69.91 H:5.87 N:10.52

Found (%) C:69.51 H:5.82 N:10.51

EXAMPLE 554-[2-[4-[bis(4-fluorophenyl)methyl]piperazino]ethoxy]-6-methyl2-(4-trifluoromethylphenyl)pyrimidine

Melting point 104.5°-106° C.

Elementary analysis for (C₃₁ H₂₉ F₅ N₄ O)

Calculated (%) C:65.49 H:5.14 N:9.85

Found (%) C:65.53 H:5.16 N:9.79

EXAMPLE 56 4-[2-(4-diphenylmethylpiperazino)ethoxy]-2-(4-methoxyphenyl)6-trifluoromethylpyrimidine

Melting point 117°-118° C.

Elementary analysis for (C₃₁ H₃₁ F₃ N₄ O₂)

Calculated (%) C:67.87 H:5.70 N:10.21

Found (%) C:67.51 H:5.65 N:10.29

EXAMPLE 574-[2-[4-[bis(4,-fluorophenyl)methyl]piperazino]ethoxy]-2-(4-methoxyphenyl)6-trifluoromethylpyrimidine

Melting point 104°-106° C.

Elementary analysis for (C₃₁ H₂₉ F₅ N₄ O₂)

Calculated (%) C:63.69 H:5.00 N:9.58

Found (%) C:63.31 H:5.15 N:9.36

EXAMPLE 58(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-hydroxyphenyl)6-methylpyrimidine maleate

Melting point 177°-179° C.

Elementary analysis for (C₁₈ H₂₁ N₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:61.82 H:5.89 N:9.83

Found (%) C:61.50 H:5.90 N:9.82

Specific rotation [α]_(D) (20° C.)=-35.77 (c=1, H₂ O)

EXAMPLE 594-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-tert-butyl-2-(4-methoxyphenyl)pyrimidinemaleate

Melting point 198°-199° C.

Elementary analysis for (C₂₂ H₂₉ N₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:64.58 H:6.88 N:8.69

Found (%) C:64.77 H:6.81 N:8.73

EXAMPLE 60(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-tert-butyl-2-(4-methoxyphenyl)pyrimidinemaleate

Melting point 203°-204° C.

Elementary analysis for (C₂₂ H₂₉ N₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:64.58 H:6.88 N:8.69 Found (%) C:64.61 H:6.93 N:8.63

Specific rotation [α]_(D) (20° C.)=-41.26 (c=1, CH₃ OH)

EXAMPLE 614-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-tert-butyl-2-(4-fluorophenyl)pyrimidinemaleate

Melting point 186°-187° C.

Elementary analysis for (C₂₁ H₂₆ FN₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:63.68 H:6.41 N:8.91

Found (%) C:63.68 H:6.42 N:8.85

EXAMPLE 62(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-6-tert-butyl-2-(4-fluorophenyl)pyrimidinemaleate

Melting point 203°-205° C.

Elementary analysis for (C₂₁ H₂₆ FN₃ O₂ · C₄ H₄ O₄)

Calculated (%) C:63.68 H:6.41 N:8.91

Found (%) C:63.62 H:6.42 N:8.87

Specific rotation [α]_(D) (20° C.)=-30.63 (c=1, CH₃ OH)

EXAMPLE 63(R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)6-trifluoromethylpyrimidine maleate

Melting point 172°-173.5° C.

Elementary analysis for (C₁₈ H₁₇ F₄ N₃ O · C₄ H₄ O₄)

Calculated (%) C:54.66 H:4.38 N:8.69

Found (%) C:54.43 H:4.38 N:8.78

Specific rotation [α]_(D) (20° C.)=-41.54 (c=1, CH₃ OH)

EXAMPLE 644-[2-[4-bis(4-fluorophenyl)methyl]piperazino]ethoxy]-2-(4-fluorophenyl)6-methylpyrimidine trihydrochloride

Melting point 176°-177° C.

Elementary analysis for (C₃₀ H₂₉ F₃ N₄ O · 3HCl)

Calculated (%) C:57.38 H:5.14 N:8.92

Found (%) C:57.16 H:5.38 N:8.73

Test Examples

Results of pharmacological tests showing the usefulness ofrepresentative compounds of the present invention are given.

Methods (1) Improvement effects on deficits of learning and memoryinduced by scopolamine.

A test drug suspended in 0.5% methyl cellulose (MC) solution wasadministered orally to ten rats in a group. 30 minutes after thistreatment, scopolamine at a dose of 0.3 mg/kg was givenintraperitoneally to the animals. 30 minutes after the treatment ofscopolamine, training trials of the step-through type passive avoidancetask were carried out. 24 hours after the trial, test trials werecarried out.

The step-through latency time in the test trial of rats was measured forup to 300 sec. The results were regarded as learning scores. (Table 1).The statistical significance compared with the control groups wasanalyzed using Kruskal-Wallis's test and Fisher's test. MC solution wasgiven to the control groups.

                  TABLE 1                                                         ______________________________________                                        Improving effects on deficits of learning and                                 memory (rats)                                                                 Drugs                                                                         (Example NO.)                                                                             Dose p.o.     Latency (sec.)                                      ______________________________________                                        1           0.03          170.80 ± 44.15                                               0.1           228.20 ± 37.47**                                             0.3           247.30 ± 35.16**                                             1             242.90 ± 38.07**                                             3             255.30 ± 30.85**                                             10            253.50 ± 31.18**                                             30            182.40 ± 40.25                                   MC          --             98.30 ± 43.95                                   2           0.01          161.30 ± 46.33                                               0.03          231.40 ± 35.92*                                              0.1           253.10 ± 31.62**                                             0.3           271.00 ± 29.00**                                             1             245.40 ± 36.48**                                             3             249.60 ± 33.86**                                             10            192.60 ± 43.89                                   MC          --             90.20 ± 35.71                                   3           0.3           191.50 ± 44.37                                               1             239.90 ± 31.58*                                              3             244.20 ± 37.21**                                             10            276.70 ± 23.30**                                             30            272.10 ± 27.90**                                 MC          --            109.40 ± 41.87                                   4           1             143.90 ± 43.53                                               3             204.50 ± 40.47                                               10            245.70 ± 36.29**                                             30            279.20 ± 20.80**                                 MC          --            106.80 ± 42.66                                   6           0.1           179.80 ± 36.66                                               0.3           200.40 ± 41.39*                                              1             222.80 ± 40.06*                                              3             223.50 ± 39.45*                                              10            188.10 ± 40.24                                   MC          --             99.90 ± 43.83                                   10          1             212.70 ± 44.45                                               3             274.00 ± 26.00**                                             10            248.40 ± 34.40**                                             30            222.40 ± 39.90*                                              100           208.50 ± 38.37                                   MC          --            133.00 ± 43.62                                   13          0.3           131.10 ± 46.13                                               1             186.10 ± 46.51                                               3             286.50 ± 13.50**                                             10            245.70 ± 36.20*                                              30            242.60 ± 38.27*                                              100           169.20 ± 44.09                                   MC          --            105.50 ± 42.59                                   15          1             270.50 ± 29.50*                                  MC          --            129.00 ± 46.60                                   21          1             170.00 ± 44.05                                               3             243.50 ± 37.67*                                              10            272.70 ± 27.30**                                             30            276.90 ± 23.10**                                 MC          --            132.00 ± 45.90                                   23          0.3           156.40 ± 47.90                                               1             243.10 ± 37.93*                                              3             270.90 ± 29.10**                                             10            274.00 ± 26.00**                                             30            272.00 ± 28.00**                                 MC          --            104.40 ± 42.79                                   26          0.03          217.80 ± 41.86                                               0.1           249.30 ± 33.84*                                              0.3           271.00 ± 29.00**                                             1             274.50 ± 25.50**                                             3             273.10 ± 26.90**                                             10            271.50 ± 28.50**                                             30            185.70 ± 46.69**                                 MC          --            135.50 ± 44.95                                   27          0.01          214.90 ± 43.34                                               0.03          247.80 ± 34.80*                                              0.1           272.90 ± 27.10**                                             0.3           271.60 ± 28.40**                                             1             274.00 ± 26.00**                                             3             272.90 ± 27.10**                                             10            167.70 ± 44.20                                   MC          --            133.80 ± 45.31                                   35          0.1           153.10 ± 41.22                                               0.3           162.40 ± 40.34                                               1             253.30 ± 31.14                                               3             274.90 ± 25.10                                               10            173.20 ± 42.51                                   MC          --            166.80 ± 44.59                                   44          0.03          196.80 ± 42.16                                               0.1           272.00 ± 28.00**                                             0.3           271.40 ± 28.60**                                             1             273.30 ± 26.70**                                             3             271.00 ± 29.00**                                             10            246.60 ± 35.63*                                              30            196.70 ± 42.51                                   MC                        129.80 ± 46.35                                   58          0.01          215.90 ± 42.89                                               0.03          252.00 ± 32.42*                                              0.1           274.20 ± 25.80**                                             0.3           272.50 ± 27.50**                                             1             272.80 ± 27.20**                                             3             187.10 ± 46.11                                   MC          --            132.10 ± 45.74                                   ______________________________________                                         MC: 0.5% methyl cellulose                                                     *p<0.05                                                                       **P<0.01                                                                 

(2) Binding affinities for muscarinic receptors

The binding assay for muscarinic receptors was carried out according tothe method of Yamamura and Snyder [Yamamura, H. I. and Snyder, S. H. ;Muscarinic cholinergic binding in rat brain. Proc.Natl.Acad. Sci.U.S.A.71:1725-1729 (1974)]. Namely the receptor membrane preparationsfrom rat brain were incubated with 0.1 nM [³ H]quinuclidinyl benzilate(QNB) in mM Na/K phosphate buffer solution (pH 7.4) at 25° C. for 60minutes. The strength of the binding affinity for muscarinic receptorswas indicated as the concentration of drug required to displace 50% ofthe [³ H]QNB binding (IC₅₀). The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Binding affinities for muscarinic receptors                                   Drugs                                                                         (Example NO.)   IC.sub.50 (M)                                                 ______________________________________                                         1              7.8 ± 10.sup.-6                                             2              3.5 ± 10.sup.-6                                            15              3.3 ± 10.sup.-6                                            26              2.9 ± 10.sup.-6                                            27              1.6 ± 10.sup.-6                                            29              1.6 ± 10.sup.-6                                            44              1.4 ± 10.sup.-6                                            51              2.7 ± 10.sup.-6                                            58              9.9 ± 10.sup.-5                                            59              7.2 ± 10.sup.-6                                            61              5.8 ± 10.sup.-6                                            62              7.4 ± 10.sup.-6                                            63              3.7 ± 10.sup.-6                                            carbachol       1.0 ± 10.sup.-4                                            pilocarpine     8.3 ± 10.sup.-6                                            ______________________________________                                    

The compounds of the present invention exhibited equivalent or superiorbinding affinities for the central muscarinic receptors compared withpilocarpine or carbachol.

(3) Effect on muscarinic M₁ receptors

Binding assay for muscarinic M₁ receptors was carried out according tothe method of Watson and Yamamura [Life Sci. 3001-3011(1983)]. Namely,the receptor membrane preparations from rat brain were incubated with 1nM [³ H]pirenzepine in 10 mM Na/K phosphate buffer solution (pH 7.4) at25° C. for 60 minutes. 1 μM of atropine was used as a displacer. Thedegree of binding affinities for muscarinic M₁ receptors were shown intable 3 as the concentration of drug which was required to displace 50%of the [³ H]pirenzedine binding (IC₅₀).

                  TABLE 3                                                         ______________________________________                                        Effects on muscarinic M.sub.1 receptors                                       Drugs                                                                         (Example NO.)   IC.sub.50 (M)                                                 ______________________________________                                         2              6.5 ± 10.sup.-7                                            27              1.7 ± 10.sup.-7                                            44              2.4 ± 10.sup.-7                                            58              8.1 ± 10.sup.-7                                            60              3.1 ± 10.sup.-6                                            62              2.8 ± 10.sup.-6                                            63              6.0 ± 10.sup.-7                                            carbachol       1.2 ± 10.sup.-5                                            ______________________________________                                    

As shown in table 3, the compounds of the present invention exhibitedinhibitory effects on the binding of [³ H]pirenzepine to M₁ receptors.These effects were 10 to 100 times more potent than that of carbachol.

(4) Acute toxicity

Male mice, 6 weeks of age (4 mice/group) were deprived of foodsovernight. Test drugs suspended in 0.5% methyl cellulose solution wereadministered orally to the mice. Whether the animals were dead or notwas observed 72 hours after the treatment of the drugs. The results wereshown in table 4.

                  TABLE 4                                                         ______________________________________                                        Acute toxicity (mice, p.o.)                                                   Drugs                                                                         (Example NO.)  Dose (mg/kg)                                                                              Lethality                                          ______________________________________                                         3             1000        0/4                                                 4             1000        0/4                                                11             1000        0/4                                                13             1000        0/4                                                21             1000        0/4                                                35             1000        0/4                                                44             1000        0/4                                                58             1000        0/4                                                ______________________________________                                         (Number of dead animals/Number of animals used)                          

It is clear from the table 4 that no death was observed when all of thecompounds of the present invention administered to the animals at a doseof 1000 mg/kg. Pharmaceutical examples

Pharmaceutical preparations using the compounds of the present inventionare as follows.

Pharmaceutical example 1 Injection

The injection in which the following prescription contained in 1 ml ofan ampule was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 2                                                                       1 mg                                                        sodium chloride   9 mg                                                        water for injection                                                                             q.s.                                            ______________________________________                                    

Pharmaceutical example 2 Injection

The injection in which the following prescription contained in 1 ml ofan ampule was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 27                                                                       1 mg                                                       sodium chloride    9 mg                                                       water for injection                                                                              q.s.                                           ______________________________________                                    

Pharmaceutical example 3 Injection

The injection in which the following prescription contained in 1 ml ofan ampule was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 44                                                                       1 mg                                                       sodium chloride    9 mg                                                       water for injection                                                                              q.s.                                           ______________________________________                                    

Pharmaceutical example 4 Injection

The injection in which the following prescription contained in 1 ml ofan ampule was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 58                                                                       1 mg                                                       sodium chloride    9 mg                                                       water for injection                                                                              q.s.                                           ______________________________________                                    

Pharmaceutical example 5 Oral liquid preparation

The oral liquid in which the following prescription contained in 100 mlwas prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 2                                                                       20 mg                                                       simple syrup      q.s.                                            ______________________________________                                    

Pharmaceutical example 6 Oral liquid preparation

The oral liquid in which the following prescription contained in 100 mlwas prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 27                                                                       20 mg                                                      simple syrup       q.s.                                           ______________________________________                                    

Pharmaceutical example 7 Oral liquid preparation

The oral liquid in which the following prescription contained in 100 mlwas prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 44                                                                       20 mg                                                      simple syrup       q.s.                                           ______________________________________                                    

Pharmaceutical example 8 oral liquid preparation

The oral liquid in which the following prescription contained in 100 mlwas prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 58                                                                       20 mg                                                      simple syrup       q.s.                                           ______________________________________                                    

Pharmaceutical example 9 Solid formulation

The tablet in which the following prescription contained in 120 mg ofone tablet was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 2                                                                        1 mg                                                       lactose           60 mg                                                       cornstarch        30 mg                                                       crystalline cellulose                                                                           20 mg                                                       hydroxypropylcellulose                                                                           7 mg                                                       magnesium stearate                                                                               2 mg                                           ______________________________________                                    

Pharmaceutical example 10 Solid formulation

The tablet in which the following prescription contained in 120 mg ofone tablet was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 27                                                                        1 mg                                                      lactose            60 mg                                                      cornstarch         30 mg                                                      crystalline cellulose                                                                            20 mg                                                      hydroxypropylcellulose                                                                            7 mg                                                      magnesium stearate  2 mg                                          ______________________________________                                    

Pharmaceutical example 11 Solid formulation

The tablet in which the following prescription contained in 120 mg ofone tablet was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 44                                                                        1 mg                                                      lactose            60 mg                                                      cornstarch         30 mg                                                      crystalline cellulose                                                                            20 mg                                                      hydroxypropylcellulose                                                                            7 mg                                                      magnesium stearate  2 mg                                          ______________________________________                                    

Pharmaceutical example 12 Solid formulation

The tablet in which the following prescription contained in 120 mg ofone tablet was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 58                                                                        1 mg                                                      lactose            60 mg                                                      cornstarch         30 mg                                                      crystalline cellulose                                                                            20 mg                                                      hydroxypropylcellulose                                                                            7 mg                                                      magnesium stearate  2 mg                                          ______________________________________                                    

Pharmaceutical example 13 Solid formulation

The powder in which the following prescription contained in 1 g wasprepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 2                                                                       2 mg                                                        lactose           996 mg                                                      Aerosil           2 mg                                            ______________________________________                                    

Pharmaceutical example 14 Solid formulation

The powder in which the following prescription contained in 1 g wasprepared according to the usual method.

    ______________________________________                                        Prescription                                                                             The compound of Example 27                                                                       2 mg                                                       lactose            996 mg                                                     Aerosil            2 mg                                            ______________________________________                                    

Pharmaceutical example 15 Solid formulation

The powder in which the following prescription contained in 1 g wasprepared according to the usual method.

    ______________________________________                                        Prescription                                                                             The compound of Example 44                                                                       2 mg                                                       lactose            996 mg                                                     Aerosil            2 mg                                            ______________________________________                                    

Pharmaceutical example 16 Solid formulation

The powder in which the following prescription contained in 1 g wasprepared according to the usual method.

    ______________________________________                                        Prescription                                                                             The compound of Example 58                                                                       2 mg                                                       lactose            996 mg                                                     Aerosil            2 mg                                            ______________________________________                                    

Pharmaceutical example 17 Suppository

The suppository in which the following prescription contained in 2g ofone suppository was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 2                                                                       2 mg                                                        suppository base  q.s.                                            ______________________________________                                    

Pharmaceutical example 18 Suppository

The suppository in which the following prescription contained in 2 g ofone suppository was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 27                                                                       2 mg                                                       suppository base   q.s.                                           ______________________________________                                    

Pharmaceutical example 19 Suppository

The suppository in which the following prescription contained in 2 g ofone suppository was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 44                                                                       2 mg                                                       suppository base   q.s.                                           ______________________________________                                    

Pharmaceutical example 20 Suppository

The suppository in which the following prescription contained in 2 g ofone suppository was prepared according to the usual method.

    ______________________________________                                        Prescription                                                                              The compound of Example 58                                                                       2 mg                                                       suppository base   q.s.                                           ______________________________________                                    

EFFECTS OF THE INVENTION

The compounds of the present invention are useful as reactivators ofacetylcholinergic nervous system since they show eminent improvementeffects on learning and memory disorders as well as have potent bindingaffinities for muscarinic receptors. Also, their safety margins are verywide.

The compounds of the present invention have superior effects that is notdemonstrated in other known drugs, and also those have wider safetymargins. Therefore those can be used as therapeutic drugs for seniledementia or as well as dementia and the like disease accompanied bymental-growth retardation, sequelae of encephalitis, cerebral palsy,cerebral apoplexy, cerebral arteriosclerosis, head injury and so forth.

We claim:
 1. A compound of the formula ##STR18## or a pharmacologicallyacceptable salt thereof wherein A and B are as follows:When A represents##STR19## B represents methyl, trifluoromethyl, or tert-butyl; when Brepresents ##STR20## A represents methyl, trifluoromethyl, or tert-butylwherein R¹ and R² are the same or different and each is hydrogen,hydroxy, lower alkoxy, trifluoromethyl or halogen; R³ represents##STR21## wherein Y represent O or NH, or ##STR22## wherein Y representsO or NH, m is 2 or 3, and R⁶ and R⁷ form a 5 to 6 membered cyclic-aminogroup with the adjacent nitrogen atom, wherein said cyclic-amino groupoptionally includes an oxygen or sulfur atom, and said cyclic-aminogroup being unsubstituted or substituted by aryl with or withoutsubstituent(s), aralkyl with or without substituent(s) wherein the alkylmoiety thereof is lower alkyl, or aroyl with or without substituent(s).2. A compound according to claim 1, wherein A represents ##STR23## B ismethyl, wherein R¹ and R² are the same or different and each ishydrogen, halogen or alkoxy of 1 to 4 carbon atoms;and further whereinR³ is 3-quinuclidinyloxy, or piperidinoethoxy or piperidinopropoxysubstituted with an aryl with or without substituent(s).
 3. A compoundaccording to claim 2, wherein R³ is 3-quinuclidinyloxy, orpiperidinoethoxy or piperidinopropoxy substituted with an aralkyl withor without substituent(s).
 4. The compound according to claim 1, whichis 4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)-6-methylpyrimidine.
 5. Thecompound according to claim 1, which is (R)-(-)4-(1-azabicyclo[2,2,2]octo-3-ylyoxy) 2-(4-fluorophenyl)-6-methylpyrimidine.
 6. Thecompound according to claim 1, which is 4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl)-6-methylpyrimidine.
 7. Thecompound according to claim 1, which is (R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl) 6-methylpyrimidine.
 8. A methodfor treating dementia in animals and humans, which comprisesadministering to an animal or human in need thereof a therapeuticallyeffective amount of a compound of the formula ##STR24## or apharmacologically acceptable salt thereof wherein A and B are asfollows:When A represents ##STR25## B represents methyl,trifluoromethyl, or tert-butyl; when B represents ##STR26## A representsmethyl, trifluoromethyl, or tert-butyl wherein R¹ and R² are the same ordifferent and each is hydrogen, hydroxy, lower alkoxy, trifluoromethylor halogen; R³ represents ##STR27## wherein Y represents O or NH,##STR28## wherein Y represents O or NH, m is 2 or 3, R⁶ and R⁷ form a 5to 6 membered cyclic-amino group with the adjacent nitrogen atom whereinthese cyclic-amino groups optionally include oxygen or sulfur atom, andare unsubstituted or substituted by aryl with or without substituent(s),aralkyl with or without substituent(s) wherein the alkyl moiety is loweralkyl, or aroyl with or without substituent(s).
 9. A method according toclaim 8, wherein A represents ##STR29## B is methyl, wherein R¹ and R²are the same or different and each is hydrogen, halogen or alkoxy of 1to 4 carbon atoms;and further wherein R³ is 3-quinuclidinyloxy, orpiperidinoethoxy or piperidinopropoxy substituted with an aryl with orwithout substituent(s).
 10. A method according to claim 9, wherein R³ is3-quinuclidinyloxy, or piperidinoethoxy or piperidinopropoxy substitutedwith an aralkyl with or without substituent(s).
 11. A method accordingto claim 8, wherein the compound is 4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl) 6-methylpyrimidine.
 12. A methodaccording to claim 8, wherein the compound is (R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy) 2-(4-fluorophenyl)-6-methylpyrimidine.
 13. A methodaccording to claim 8, wherein the compound is 4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl) 6-methylpyrimidine.
 14. A methodaccording to claim 10, wherein the compound is (R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl) 6-methylpyrimidine.
 15. Themethod of claim 8, wherein R³ represents Y-(CH₂)_(m) N(R⁶)(R⁷), whereinR⁶ and R⁷ are lower alkyl or R⁶ and R⁷ together with the adjacentnitrogen atom form piperidino, and Y and m are as defined in claim 10.16. The method of claim 8, wherein said compound is4-[2-(N,N-diethylamino)ethoxy]-6-methyl-2-phenylpyrimidine or apharmaceutically acceptable salt thereof.
 17. The method of claim 8,wherein said compound is2-(4-methoxyphenyl)-4-methyl-6-[2-(4-phenylpiperidino)ethoxy]-pyrimidineor a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition for treating dementia in animals and humans, which comprisesa therapeutically effective amount of a compound of the formula##STR30## or a pharmacologically acceptable salt thereof wherein A and Bare as follows:When A represents ##STR31## B represents methyl,trifluoromethyl, or tert-butyl, when B represents ##STR32## A representsmethyl, trifluoromethyl, or tert-butyl wherein R¹ and R² are the same ordifferent and each is hydrogen, hydroxy, lower alkoxy, trifluoromethylor halogen; R³ represents ##STR33## wherein Y represents O or NH, or##STR34## wherein Y represents O or NH, m is 2 or 3, and R⁶ and R⁷ forma 5 to 6 membered cyclic-amino group with the adjacent nitrogen atomwherein said cyclic-amino groups optionally include an oxygen or sulfuratom, and said cyclic amino group being unsubstituted or substituted byaryl with or without substituent(s), aralkyl with or withoutsubstituent(s) wherein the alkyl moiety is lower alkyl, or aroglorwithout substituent(s), in combination with a pharmaceuticallyacceptable inert diluent or carrier.
 19. A pharmaceutical compositionaccording to claim 18, whereinA represents ##STR35## B is methyl,wherein R¹ and R² are the same or different and each is a hydrogen,halogen or alkoxy of 1 to 4 carbon atoms; and further wherein R³ is3-quinuclidinyloxy, or piperidinoethoxy or piperidinopropoxy substitutedwith an aryl with or without substituent(s).
 20. A pharmaceuticalcomposition according to claim 19, wherein R³ is 3-quinuclidinyloxy, orpiperidinoethoxy or piperidinopropoxy substituted with an aralkyl withor without substituent(s).
 21. A pharmaceutical composition according toclaim 18, wherein the compound is 4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)-6-methylpyrimidine.
 22. Apharmaceutical composition according to claim 18, wherein the compoundis (R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-fluorophenyl)-6-methylpyrimidine.
 23. Apharmaceutical composition according to claim 18, wherein the compoundis 4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl)-6-methylpyrimidine.
 24. Apharmaceutical composition according to claim 18, wherein the compoundis (R)-(-)-4-(1-azabicyclo[2,2,2]octo-3-yloxy)-2-(4-chlorophenyl)-6-methylpyrimidine.